After AIDS, tuberculosis (TB) is the leading cause of adult mortality (2-3 million deaths per year) in the world and is a critical impediment to alleviating global poverty and suffering (1). Factors contributing to the resurgence of the disease include difficulties in implementing anti-TB programs in many countries, the dramatic increase in the number of immunosuppressed individuals—due mainly to HIV infection—and the movement of people through and from areas where TB is endemic. The TB and HIV epidemics fuel one another in co-infected people—currently 11 million adults—increasing both morbidity and mortality (2, 3). In addition, TB is the leading cause of death in HIV-infected people (4).
Although first-line anti-TB drug regimens can achieve more than 90% efficacy rates, their complexity can lead to poor compliance when adequate medical support and TB treatment programs are not available and, in turn, to the emergence of resistance (5). Multidrug-resistant (MDR) strains of TB complicate treatment substantially (6). The Global Alliance for TB Drug Development has recommended that any new treatment should offer at least one of the following three advantages over existing therapies: shortening or simplifying effective treatment of TB; increasing efficacy against MDR-TB; and improving treatment of the latent form of TB infection. Such a new drug would greatly improve patient compliance, thereby reducing the cost of TB treatment programs like the World Health Organization (WHO)'s Directly Observed Treatment Short-course (DOTs) strategy (7).
Newer anti-TB candidates currently in preclinical and clinical development tend to be either from existing families of drugs (such as moxifloxacin), or analogs of first-line drugs such as MJH-98-1-81 (from isoniazid), the oxazolidinones, and rifapentine (a close analog of rifampin) (8). Although these new drugs may be potent, analog compounds provide only temporary solutions to resistance (9), as they rely on the same mechanism of action as the existing families of drugs.
Antibiotics in general usually inhibit bacterial replication by inhibiting bacterial metabolism though a specific mechanism. For example, isoniazid interferes with the enzymatic machinery that synthesizes mycolic acids, necessary components of the cell wall, while rifampicin interferes with the bacterial machinery for transcribing RNA from DNA. It is accordingly of interest to explore novel methods to identify anti-TB compounds that target different mycobacterial specific aspects of cell growth and replication compared to the known agents.